Endometrial cancer includes all forms and subtypes of the disease, including for example, serous, mucinous, and endometrioid histological subtypes or any other cancer that starts in the endometrium, which includes the lining of the uterus. Particularly, cancer of the endometrium is the most common gynecologic malignancy and accounts for 6% of all cancers in women. It is estimated there were ˜46,000 new cases diagnosed and ˜8,000 women dying from this disease in 2011 in the USA. Although early diagnosis largely explains the relatively good overall long-term survival of EC, the 5-year survival rates for women with regional or distant metastatic disease at diagnosis is only ˜70% and ˜25% respectively. Worse is the outcome for patients with early stage cancers that subsequently recur (5 year survival of ˜13%).
Members of the fibroblast growth factor receptor (FGFR) tyrosine kinase family have been shown to be amplified or mutationally activated in endometrial cancer and a variety of other cancer types, including breast cancer, ovarian cancer, lung cancer, gastric cancer, bladder cancer, glioblastoma and rhabdomyosarcoma, making FGFRs an attractive potential therapeutic target. Targeted tyrosine kinase inhibitors (TKIs) have shown success in cancer treatment. However, the long-term efficacy of these TKIs is frequently limited by development of resistance to the TKIs. The resistance developed to TKIs can be due to mutation of the target kinase. It has been shown that shRNA knockdown and kinase inhibition with PD173074 (research only pan-FGFR inhibitor) induced G1 growth arrest and cell death in two FGFR-mutant EC lines (AN3CA and MFE280). Preclinical studies have demonstrated that FGFR inhibition is a viable therapeutic strategy in not only EC, but also a range of malignancies driven by FGFR amplification or mutation, which include breast, endometrial and gastric cancers. However, the remarkable success of small molecule tyrosine kinase inhibitors in the clinic, such as imatinib, has been tempered by the presence of both primary resistance in a subset of patients and the emergence of secondary resistance (acquired resistance) in some, if not all, patients.
Despite the importance of FGFRs as cancer drug targets, little is known about the repertoire of mutations in FGFRs that confer resistance to current FGFR inhibitors. Therefore, there is a need to determine specific resistance profiles for each particular compound by discovering relevant mutation(s) in FGFR. With such a resistance profile, it is possible to identify the drug most likely to benefit patients not only broadly, but also based on their individual spectrum of potential intrinsic resistance, rather than merely the best anti-FGFR agent. Such FGFR mutation(s) can be used to screen for new generations of FGFR inhibitor, whether it is an FGFR-specific inhibitor, or a multi-targeted protein kinase inhibitor, or a combination of selective antagonists, as in an anti-tumor or anti-cancer drug, and subject a patient to a specific treatment that would be responsive.